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- Title
Analysis of the Thyrotropin Receptor-Thyrotropin Interaction by Comparative Modeling.
- Authors
Ricardo Núñez Miguel; Jane Sanders; Jennifer Jeffreys; Hilde Depraetere; Michele Evans; Tonya Richards; Tom L. Blundell; Bernard Rees Smith; Jadwiga Furmaniak
- Abstract
We have used the most advanced programs currently available to construct the first three-domain structure ofthe human thyrotropin receptor (TSHR) using comparative modeling. The model consists of a leucine-rich domain(LRD; amino acids 36–281; porcine ribonuclease inhibitor used as a template for modeling), a cleavage domain(CD; amino acids 282–409; tissue inhibitor of matrix metalloproteinases 2 as template) and transmembranedomain (TMD amino acids 410–699; bovine rhodopsin as template). Models of human, porcine, and bovine TSHwere also constructed (human chorionic gonadotropin [hCG] and human follicle stimulating hormone [hFSH]as templates). The LRD has a characteristic horseshoe shape with 10 tandem homologous repeats. The CD consistsof β-barrel and α helix structures (OB-like fold) with two disulfide bridges and the structure around thesedisulfide bridges remains stable after cleavage. The TMD presents the typical seven membrane-spanning helices.The TSH, LRD, CD, and TMD models were brought together in an extensive series of docking experiments.Known features of the TSH–TSHR interaction were used for selection of appropriate complexes that were thenvalidated using a different set of experimental data. A similar approach was used to build a model of a complexbetween the TSHR and a monoclonal TSHR antibody with weak thyroid stimulating activity. Human thyrotropin(hTSH) α chains were found to make contact with many amino acids on the LRD surface and CD surfacewhereas no interaction between the β chains and the CD were found. The higher affinity of bovine thyrotropin(bTSH) and porcine thyrotropin (pTSH) (relative to hTSH) for the TSHR is explained well by the models in termsof charge–charge interactions between their α chains and the receptor. Experimental observations showing increasedsensitivity of the TSHR to hCG after mutation of TSHR Lys209 to Glu are explained well by our model.Furthermore, several mutations in the TMD that are associated with increased TSHR basal activity are predictedfrom our model to be caused by the formation of new interactions that stabilize the activated form of the TMD.
- Publication
Thyroid, 2004, Vol 14, Issue 12, p991
- ISSN
1050-7256
- Publication type
Article